We have developed a macaque model for maternal-fetal transmission by infecting Macaca nemestrina (pig-tailed macaque) with pathogenic simian immunodeficiency virus (SIV/Mne). Nine pregnant pig-tailed macaques were infected intravenously with SIV during the first, second, or third trimester. All three mothers infected during the first trimester aborted their offspring. The six mothers infected during the second and third trimester delivered full-term infants; two of the six were shown to be SIV-infected and died of AIDS three and six months after birth. The incidence of maternal-fetal transmission of this study was 33%, similar to that observed in humans. Preliminary data based on viral load in the peripheral blood lymphocytes (PBLs) at birth are consistent with infection occurring shortly before or during birth. This model of maternal-fetal transmission will allow us to study the time of viral transfer (by sampling fetal tissue before birth), the effect of maternal antibodies on viral transmission, and the effect of vaccines or antivirals on the prevention of transmission. To more closely approximate one of the naturally occurring mechanisms of HIV transmission, we have inoculated macaques intrarectally with various dilutions of cell-free SIV. The dose of virus required for a serological response to infection was a thousand times larger than the dose required after intravenous infection. Some intrarectally inoculated animals, infected with doses of virus below the threshold required for seroconversion, developed CD4 depletion 3 1/2 years following infection. Virus could occasionally be isolated from PBLs, but the virus load was so low that the animals' lymph node cells and PBLs were polymerase chain reaction negative, as tested with nested primers in the long terminal repeat region of the virus. These results, if applicable to the intrarectal transmission of HIV, would have public health consequences in the management of patients at risk.